Mithplatins: Mithramycin SA-Pt(II) Complex Conjugates for the Treatment of Platinum-Resistant Ovarian Cancers |
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| Authors: | Dr Suhas S Bhosale Dr Abhisek Mandal Dr Caixia Hou J Robert McCorkle Dr David Schweer Dr Kristen S Hill Vivekanandan Subramanian Dr Jill M Kolesar Prof Oleg V Tsodikov Prof Jürgen Rohr |
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| Affiliation: | 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone Street, Lexington, KY, 40536 USA;2. Markey Cancer Center, University of Kentucky, 760 S. Rose Street, Lexington, KY, 40536 USA;3. Division of Gynecologic Oncology, College of Medicine, 760 S. Rose Street, Lexington, KY, 40536 USA;4. University of Kentucky PharmNMR Center, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0596 USA |
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| Abstract: | DNA coordinating platinum (Pt) containing compounds cisplatin and carboplatin have been used for the treatment of ovarian cancer therapy for four decades. However, recurrent Pt-resistant cancers are a major cause of mortality. To combat Pt-resistant ovarian cancers, we designed and synthesized a conjugate of an anticancer drug mithramycin with a reactive Pt(II) bearing moiety, which we termed mithplatin. The conjugates displayed both the Mg2+-dependent noncovalent DNA binding characteristic of mithramycin and the covalent crosslinking to DNA of the Pt. The conjugate was three times as potent as cisplatin against ovarian cancer cells. The DNA lesions caused by the conjugate led to the generation of DNA double-strand breaks, as also observed with cisplatin. Nevertheless, the conjugate was highly active against both Pt-sensitive and Pt-resistant ovarian cancer cells. This study paves the way to developing mithplatins to combat Pt-resistant ovarian cancers. |
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| Keywords: | Ovarian cancer Mithramycin Platinum resistance DNA cross linking Platinum complexes |
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